# The role of endothelial cells in the formation of early metastatic niches in the lung

> **NIH NIH R56** · UNIVERSITY OF PENNSYLVANIA · 2021 · $16,916

## Abstract

SUMMARY
Metastatic disease is a multistep cascade and is the primary cause of cancer-related mortalities. Many studies
are investigating how tumor cells acquire the ability to metastasize to distant organs and escape from their
primary location. However much less is known about the mechanisms underlying the colonization of normal
organs by disseminated and circulating tumor cells, arguably the rate limiting step in metastatic progression. The
lung is one of the most common sites of metastases therefore in this proposal, we will investigate the role of
endothelial cells (ECs) in the normal lung during extravasation of circulating cancer cells out of the vessel lumen
and colonization into the normal lung to establish lung metastases. Disseminated tumor cells undergo significant
stress in the circulation such that during extravasation into the normal lung, they require a protective niche
composed of extracellular matrix to provide physical anchorage to prevent anoikis and apoptosis. This protective
niche allows disseminated tumor cells the opportunity to recover, survive and expand in the lung eventually
becoming macrometastatic lesions. We are investigating the processes that activate lung ECs converting normal
lung tissue into hospitable “soil” or an early metastatic niche (EMN) to facilitate colonization by circulating tumor
cells. Our published studies and preliminary data suggest that lung ECs are activated prior to the arrival of tumor
cells in mouse models of lung metastases. Our data also indicate that the matricellular glycoprotein,
thrombospondin-1 (TSP1) plays an important role in regulating EC homeostasis during metastatic progression.
Tumor cells that specifically metastasize to the lung and tumor conditioned media downregulates TSP1 in lung
ECs promoting EC activation. Our pilot studies identified increased expression of matrix metalloproteases
(MMPs) 3 in TSP1low ECs. Our preliminary data suggest that MMP3 promotes endothelial-to-mesenchymal
through interactions with CD44 ultimately leading to increased extracellular matrix production and remodeling
contributing to EMN generation in the lung. Our overarching hypothesis is that
primary tumors that
metastasize to the lung activate lung ECs by TSP1 downregulation leading to EndoMT and increased
extracellular matrix production in the EMN supporting lung colonization. We propose that TSP1 is a critical
regulator of EC homeostasis and its loss promotes EC activation and ultimately leads to extracellular matrix
production and remodeling via an MMP3-CD44 axis. Understanding the contribution of ECs in the normal lung
towards metastatic progression will offer new insight into the mechanisms underlying the earliest stages of lung
metastases and may offer therapeutic targets for the prevention of metastatic disease.

## Key facts

- **NIH application ID:** 10241023
- **Project number:** 2R56CA118374-12A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sandra Ryeom
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $16,916
- **Award type:** 2
- **Project period:** 2021-09-17 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241023

## Citation

> US National Institutes of Health, RePORTER application 10241023, The role of endothelial cells in the formation of early metastatic niches in the lung (2R56CA118374-12A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241023. Licensed CC0.

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